Graft materials for surgical breast procedures

ABSTRACT

Graft materials and devices for surgical breast procedures, as well as methods of making graft devices are described.

BACKGROUND

Graft materials can be used in a wide range of surgical procedures toaugment tissue or repair or correct tissue defects. One application ofgraft materials is the field of cosmetic and reconstructive surgicalbreast procedures, a field in which the number of procedures performedeach year continues to increase. Some graft materials are typicallyprovided to surgeons as a sheet or sheet-like material, which thesurgeon can cut to the desired size and shape before implantation. Graftmaterials can be very expensive and can pose challenges for attainingadequate conformance to underlying features of the implantation site.

Accordingly, there is a need for improved graft materials.

SUMMARY

According to certain embodiments, a graft material for surgical breastprocedures is disclosed that includes a sample of biocompatible materialwith a first edge and a second edge. The first edge has a convex portionthat curves away from the second edge, and the second edge has a convexportion that curves away from the first edge.

According to certain embodiments, a graft material for surgical breastprocedures is disclosed that includes a sample of biocompatible materialwith a set of perforations that form an arcuate pattern across at leasta portion of the sample of biocompatible material.

According to certain embodiments, a method of making one or more graftdevices is disclosed. The method includes cutting one or more samplesfrom a sheet of biocompatible material such that the samples are sizedand shaped for conforming to a portion of a surface of a breast implant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 2 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 3 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 4 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 5 is a perspective view of one exemplary embodiment of a graftmaterial, illustrated in relation to a breast implant.

FIG. 6 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 7 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 8 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 9 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 10 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 11 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 12 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 13 is a perspective view of one exemplary embodiment of a graftmaterial.

FIG. 14 is a detailed view of a set of perforations consistent with oneexemplary embodiment of a graft material.

FIG. 15 is a flow chart showing a method for treating tissue.

FIG. 16 is a flow chart showing a method for treating breast tissue.

DETAILED DESCRIPTION

Reference will now be made in detail to the present embodiments(exemplary embodiments) of the invention, examples of which areillustrated in the accompanying drawings. Wherever possible, the samereference numbers will be used throughout the drawings to refer to thesame or like parts.

In this application, the use of the singular includes the plural unlessspecifically stated otherwise. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, the use of the term“including,” as well as other forms, such as “includes” and “included,”is not limiting. Also, terms such as “element” or “component” encompassboth elements and components comprising one unit and elements andcomponents that comprise more than one subunit, unless specificallystated otherwise. Also, the use of the term “portion” may include partof a moiety or the entire moiety.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in this application,including but not limited to patents, patent applications, articles,books, and treatises, are hereby expressly incorporated by reference intheir entirety for any purpose.

The term “graft material,” as used herein, generally refers to amaterial such as, for example, tissue, processed tissue, or syntheticsthat can be attached to or inserted into a bodily part.

The terms “sheet” and “sheet-like,” as used herein, generally refer to abroad, relatively thin, surface or layer of a material. Such sheets can,but may not, be relatively flexible, and may be flat or uniform inthickness or may vary in thickness across their surface.

The terms “breast implant” and “implant,” as used herein, generallyrefer to medical devices that are implanted either under breast tissueor under the chest muscle for breast augmentation or reconstruction.Such implants can include saline filled or silicone gel implants, orother implants that provide volume for breast augmentation.

The present disclosure relates to graft materials and methods of usinggraft materials in breast or other plastic surgery procedures. The graftmaterials can be used for tissue augmentation, repair or regeneration ofdamaged tissue, and/or correction of tissue defects. As such, the graftmaterial and methods discussed herein may be suitable for a wide rangeof surgical applications. In various embodiments, the graft materialsand methods discussed herein may be suitable for various types ofsurgical breast procedures, such as, for example, aesthetic surgeryassociated with mastectomy or lumpectomy, breast reconstruction, breastaugmentation, breast enhancement, breast reduction, mastopexy, andrevisionary breast surgeries.

Various embodiments of graft materials discussed herein include a sampleof biocompatible material. In some embodiments, a sample ofbiocompatible material may be a flat sheet or sheet-like in form. Asample of biocompatible material may be a single layer or may bemulti-layered. In some embodiments, a sample of biocompatible materialmay be a material that facilitates revascularization and cellrepopulation. For example, as further described below, certainembodiments can include an acellular tissue matrix (“ATM”).

FIG. 1 provides a perspective view of one exemplary embodiment of agraft material for surgical breast procedures. The graft material maycomprise a sample of biocompatible material 13 a. Sample ofbiocompatible material 13 a can have a first edge 15 a and a second edge17 a. A portion of first edge 15 a can be convex, curving away fromsecond edge 17 a. Similarly, a portion of second edge 17 a can beconvex, curving away from first edge 15 a. As depicted in FIG. 1, firstedge 15 a and second edge 17 a may both be substantially convex, thusmaking sample of biocompatible material 13 a generally biconvex inshape.

In one exemplary embodiment, either or both first edge 15 a and secondedge 17 a may be substantially parabolicly curved. As such, thecurvature of each may be characterized, in part, by the distance fromthe focus to the vertex of each parabola. For example, as depicted inFIG. 1, first edge 15 a and second edge 17 a may be substantiallyparabolicly curved, with the parabolic curve of second edge 17 a havinga greater distance from its focus to its vertex than that of first edge15 a. Furthermore, in certain embodiments, sample of biocompatiblematerial 13 a may be implanted across breast tissue of a patient suchthat first edge 15 a is positioned lateral and inferior to first edge 17a, and such that a longitudinal axis y of sample of biocompatiblematerial 13 a is at about a 45° angle with respect to the transverseplane of the patient.

First edge 15 a and second edge 17 a may join at an apex. Depending onthe needs of the procedure, the apex can be configured in numerousshapes, such as, for example, a pointed apex 19 a, as depicted in FIG.1, a rounded apex 19 b, as depicted in FIG. 2, or a squared apex 19 c,as depicted in FIG. 3. Further, first edge 15 a and second edge 17 a maybe joined at more than one apex, and each apex may be shapeddifferently. Similarly, sample of biocompatible material 13 a may besymmetrical, for example about an axis x, as depicted in FIG. 1, orasymmetrical, such as 13 b depicted in FIG. 4.

In some exemplary embodiments, the edges of a sample of biocompatiblematerial may have multiple portions with varying degrees of curvature,including, for example, nonconvex, straight, or concave portions, inaddition to a convex portion. For example, as shown in FIG. 4, a sampleof biocompatible material 13 b may have a first edge 15 b and a secondedge 17 b joined at a first apex 19 d and a second apex 19 e. First edge15 b may have a nonconvex portion 29, and second edge 17 b may have anonconvex portion 31. The nonconvex portions of first edge 15 b andsecond edge 17 b may converge at the second apex 19 e. In certainembodiments, sample of biocompatible material 13 b may be implantedacross breast tissue of a patient such that second apex 19 e ispositioned medial and inferior to first apex 19 d, and such that alongitudinal axis y of sample of biocompatible material 13 b is at abouta 45° angle with respect to the transverse plane of the patient.Further, in some embodiments, the nonconvex portions of first edge 15 band second edge 17 b may be substantially straight.

Since graft materials may be provided in sheet or sheet-like forms, andthe underlying features of the implantation site are often rounded orirregularly shaped, it may be difficult to attain adequate conformancebetween the graft material and the underlying features. This can bechallenging in surgical breast procedures, where the desired outcomeinvolves unique aesthetic and structural demands. Specifically, it canbe difficult to avoid undesired pleating after implanting a sheet ofgraft material over a rounded breast mound and/or breast implant. Insome circumstances, pleating may be undesirable because it may beperceptible by palpation and/or it may negatively affect cellintegration or infiltration. Providing adequate support to maintainbreast shape and projection and to minimize or avoid eventual ptosis, orsagging, of the breast can also be a challenge. In some embodiments,graft materials incorporating edge configurations, as described herein,may improve surface coverage and conformance to underlying anatomicalfeatures when implanted in a patient.

In some exemplary embodiments, sample of biocompatible material 13 b maybe specifically sized and shaped to conform to a portion of a surface ofa breast implant. For example, a specific size and shape may be derivedby modeling the lower pole of a breast implant in its proper orientationwith respect to gravity. Accordingly, FIG. 5 shows a modeled Style 410Anatomical Implant (Allergan, Inc. (Santa Barbara, Calif.)) 21 in avertical orientation and a sample of biocompatible material 13 b havinga shape produced by modeling biocompatible material covering 50% ofimplant 21 such that sample of biocompatible material 13 b may bebordered by the inframammary fold, the lateral fold, and the inferioredge of the pectoralis major muscle when implanted in a patient. In someembodiments, tailoring the size and shape of the graft material to abreast implant can provide better conformance of the graft material tothe implant and/or surrounding tissue and may reduce the frequency ofpleating.

Currently, graft material is typically provided to surgeons as sheets orsheet-like devices, and the surgeon may cut the material to the desiredsize and shape before implantation. While providing flexibility tosurgeons, this practice has several drawbacks. Often, substantialamounts of the graft material can be wasted. For example, surgeons mayinaccurately estimate the size of the device needed, eitheroverestimating and disposing of the unused portion of an unnecessarilylarge device, or underestimating and necessitating the opening of asecond packaged device. Such waste can add substantial costs toprocedures, as graft materials are often very expensive and may bepriced based on the amount of material included. Furthermore, it may bedifficult for surgeons to accurately cut the material freehand into aspecific optimum shape.

In some embodiments, ready-to-use, off-the-shelf graft materials can bemade that are designed to conform to breast implants of variousspecifications. For example, in some embodiments, a sample ofbiocompatible material can be specifically sized and shaped to conformto a particular type of breast implant, such as, for example, gel orsaline, round or anatomical/contour, form-stable or nonform-stable, andsmooth or textured implants. Alternatively or additionally, a sample ofbiocompatible material can be specifically sized and shaped to conformto breast implants of a predetermined volume. For example, graftmaterials can be made from a sample of biocompatible material sized andshaped specifically for common breast implant volumes, such as, betweenabout 400 and about 550 cubic centimeters, between about 250 and about400 cubic centimeters, between about 250 and about 550 cubiccentimeters, or less than about 250 cubic centimeters. Further, a sampleof biocompatible material can be specifically shaped to conform tobreast implants of a particular profile, such as, for example, samplesof biocompatible material 13 c and 13 d, as shown in FIGS. 6 and 7.Sample of biocompatible material 13 c may be better suited for amoderate profile implant while sample of biocompatible material 13 d maybe better suited for a high profile implant. Providing graft materialsspecifically sized and shaped for breast implants of particularspecifications (e.g., volume, surface area, surface texture, material,profile, mechanical properties) may remove some of the uncertaintyassociated with a surgeon attempting to estimate the optimal size andshape of graft material needed for a particular surgery. This in turn,may reduce the amount of graft material that is sometimes wasted due toinaccurate estimates. This may also reduce the need to performtrimming/resizing of the graft material during surgery. Avoidingtrimming/resizing during surgery may reduce the duration of the surgery,which can be beneficial both for the health of the patient and forreducing the cost of the surgery.

In other exemplary embodiments, the sample of biocompatible material canbe slightly oversized relative to the modeled size and shape. Slightoversizing can allow the graft material to accommodate breast implantsof different profiles. Additionally, an identified size and shape can beslightly oversized in some portions to make the graft material generallysymmetrical, such as, for example, sample of biocompatible material 13a. While this may result in small excesses in material use, this couldaid the surgeon by making it unnecessary to identify a particular sidethat must be positioned medially or laterally.

In some embodiments, the graft material described herein can be used toassist in treating patients in whom complications related to breastimplants have arisen. Such complications can include malposition (e.g.,inframmary fold malposition, lateral malposition, symmastia), stretchdeformity, coverage issues (e.g., wrinkling and rippling), and capsularcontraction. For example, in some embodiments, the graft materialdescribed herein may be used to help control the breast pocket size andlocation, act as an “internal bra” to hold the implant in place, supportfold repairs, support the implant to reduce the pressure and tension onpatient's own tissue, and/or provide an additional layer for coverage ofthe implant.

Exemplary embodiments may further include one or more sets ofperforations across at least a portion of the sample of biocompatiblematerial. Perforations can be formed in the sample of biocompatiblematerial by any suitable method, such as, for example, die cutting,laser drilling, water jet cutting, skin graft meshing, or manualincision (e.g., with a scalpel). In some exemplary embodiments, such aset of perforations can be used to improve the conformance of a sampleof biocompatible material to anatomical structures and/or a breastimplant. For example, as depicted in FIG. 8, set of perforations 23 amay form an arcuate pattern across sample of biocompatible material 13e. In some exemplary embodiments, the arcuate pattern can improveconformance of graft materials to rounded structures, such as, forexample, breast tissue. In certain embodiments, set of perforations 23 amay create a mesh pattern that enables separation and/or expansion ofportions of biocompatible material 13 e such that portions ofbiocompatible material 13 e may be capable of covering larger surfaceareas. In some exemplary embodiments, one or more sets of perforationsacross at least a portion of the sample of biocompatible material mayalso be used to modify the mechanical properties of the sample ofbiocompatible and/or affect tissue ingrowth.

In various embodiments, one or more sets of perforations can beincorporated into graft material in numerous configurations depending onthe structure of the tissue on which the graft material is to beimplanted or type of breast implant being used. For example, a set ofperforations 23 a can be included on samples of biocompatible materialof any desired shape, such as, for example, semicircular (13 e, 13 f)(including semicircular with a portion removed, as depicted in FIG. 9,to accommodate an anatomical feature, such as, for example, thenipple-areola complex), rectangular (13 g), or customized to a breastimplant (13 b), as described above in greater detail. The set ofperforations may be uniform or irregular in shape and spacing. A set ofperforations may include individual perforations that are arcuate,individual perforations that are straight but arranged in an arcuatepattern, or a combination of both, depending on the features of theimplantation surface. Individual perforations can be formed as slits,circular apertures, or any other shape. Furthermore, set of perforations23 a can be placed across an entire surface of biocompatible material 13g, as depicted in FIG. 10, or simply a portion of a surface ofbiocompatible material 13 g, as depicted in FIG. 11, in order to achievedesired conformance characteristics across different portions of thesample of biocompatible material 13 g. Similarly, as depicted in FIG.13, multiple sets of perforations 23 b, 23 c can be included on a singlesample of biocompatible material to attain a desired variation ofconformance characteristics across the sample of biocompatible material.

In some exemplary embodiments, as depicted in FIG. 14, a uniform set ofperforations may include a series of parallel slits 25. Each slit 25 mayhave a generally uniform length L, adjacent slits may be separatedlongitudinally by a generally uniform gap distance g, and adjacentparallel slits may be separated by a generally uniform horizontalseparation distance d. In some exemplary embodiments, length L may bebetween about 0.1 and about 20 millimeters, gap distance g may bebetween about 0.1 and about 20 millimeters, and horizontal separationdistance d may be between about 0.1 and about 20 millimeters. Further,in some exemplary embodiments, length L may be between about 4 and about8 millimeters, gap distance g may be between about 2 and about 6millimeters, and horizontal separation distance d may be between about 2and about 6 millimeters. In some exemplary embodiments, adjacentparallel slits may be offset longitudinally with respect to each otheras depicted in FIG. 14. Such a configuration of a set of parallel slitsmay provide improved conformance to a sample of biocompatible materialwhile still maintaining sufficient support strength.

In some embodiments, the samples of biocompatible material can compriseany suitable synthetic or biologic material, such as, for example,medical-grade silicon, autologous or cadaveric tissue, and/orbiomatrices, such as, for example, ATM.

As used herein, ATM refers to a tissue-derived biomatrix structure thatcan be made from any of a wide range of collagen-containing tissues byremoving all, or substantially all, viable cells and all detectablesubcellular components and/or debris generated by killing cells. As usedherein, an ATM lacking “substantially all viable cells” is an ATM inwhich the concentration of viable cells is less than 1% (e.g., lessthan: 0.1%; 0.01%; 0.001%; 0.0001%; 0.00001%; or 0.000001%) of that inthe tissue or organ from which the ATM was made.

ATM's that are suitable for use in the present disclosure include thosethat contain, lack, or substantially lack, an epithelial basementmembrane. As used herein, an ATM that “substantially lacks” anepithelial basement membrane is an acellular tissue matrix containingless than 5% (e.g., less than: 3%; 2%; 1%; 0.5%; 0.25%; 0.1%; 0.01%;0.001%; or even less than 0.0001%) of the epithelial basement membranepossessed by the corresponding unprocessed tissue from which theacellular tissue matrix was derived.

An epithelial basement membrane is a thin sheet of extracellularmaterial contiguous with the basilar aspect of epithelial cells. Sheetsof aggregated epithelial cells form an epithelium. Thus, for example,the epithelium of skin is called the epidermis, and the skin epithelialbasement membrane lies between the epidermis and the dermis. Theepithelial basement membrane is a specialized extracellular matrix thatprovides a barrier function and an attachment surface forepithelial-like cells; however, it does not contribute any significantstructural or biomechanical role to the underlying tissue (e.g.,dermis). Components of epithelial basement membranes include, forexample, laminin, collagen type VII, and nidogen. The temporal andspatial organizations of the epithelial basement membrane distinguish itfrom, e.g., the dermal extracellular matrix.

Accordingly, in some non-limiting embodiments, the ATMs suitable for usein the present disclosure contain epithelial basement membrane. In othernon-limiting embodiments, ATM may lack or substantially lack epithelialbasement membrane.

ATM's suitable for use in the present disclosure may, for example,retain certain biological functions, such as cell recognition, cellbinding, the ability to support cell spreading, cell proliferation,cellular in-growth and cell differentiation. Such functions may beprovided, for example, by undenatured collagenous proteins (e.g., type Icollagen) and a variety of non-collagenous molecules (e.g., proteinsthat serve as ligands for either molecules such as integrin receptors,molecules with high charge density such as glycosaminoglycans (e.g.,hyaluronan) or proteoglycans, or other adhesins). In some embodiments,the ATM's may retain certain structural functions, including maintenanceof histological architecture and maintenance of the three-dimensionalarray of the tissue's components. The ATM's described herein may also,for example, exhibit desirable physical characteristics such asstrength, elasticity, and durability, defined porosity, and retention ofmacromolecules.

ATMs suitable for use in the present disclosure may be crosslinked oruncrosslinked.

The efficiency of the biological functions of an ATM can be measured,for example, by the ability of the ATM to support cell proliferation. Insome embodiments of the present disclosure, the ATM exhibits at least50% (e.g., at least: 50%; 60%; 70%; 80%; 90%; 95%; 98%; 99%; 99.5%;100%; or more than 100%) of that of the native tissue or organ fromwhich the ATM is made.

In some embodiments, the graft material is amenable to being remodeledby infiltrating cells such as differentiated cells of the relevant hosttissue, stem cells such as mesenchymal stem cells, or progenitor cells.This may be accomplished, for example, by forming the grafted matrixmaterial from tissue that is identical to the surrounding host tissue,but such identity is not necessary.

Remodeling may be directed by the above-described ATM components andsignals from the surrounding host tissue (such as cytokines,extracellular matrix components, biomechanical stimuli, andbioelectrical stimuli). For example, the presence of mesenchymal stemcells in the bone marrow and the peripheral circulation has beendocumented in the literature and shown to regenerate a variety ofmusculoskeletal tissues [Caplan (1991) J. Orthop. Res. 9:641-650; Caplan(1994) Clin. Plast. Surg. 21:429-435; and Caplan et al. (1997) ClinOrthop. 342:254-269]. Additionally, the graft must provide some degree(greater than threshold) of tensile and biomechanical strength duringthe remodeling process.

ATM in accordance with the present disclosure may be manufactured from avariety of source tissues. For example, ATM may be produced from anycollagen-containing soft tissue and muscular skeleton (e.g., dermis,fascia, pericardium, dura, umbilical cords, placentae, cardiac valves,ligaments, tendons, vascular tissue (arteries and veins such assaphenous veins), neural connective tissue, urinary bladder tissue,ureter tissue, or intestinal tissue), as long as the above-describedproperties are retained by the matrix. Moreover, the tissues in whichATM graft material are placed may include any tissue that can beremodeled by invading or infiltrating cells. Non-limiting examples ofsuch tissues include skeletal tissues such as bone, cartilage,ligaments, fascia, and tendon. Other tissues in which any of the abovegrafts can be placed include, for example, skin, gingiva, dura,myocardium, vascular tissue, neural tissue, striated muscle, smoothmuscle, bladder wall, ureter tissue, intestine, and urethra tissue.

While an ATM may be made from one or more individuals of the samespecies as the recipient of the ATM graft, this is not necessarily thecase. Thus, for example, an ATM may be made from porcine tissue andimplanted in a human patient. Species that can serve as recipients ofATM and donors of tissues or organs for the production of the ATMinclude, without limitation, humans, nonhuman primates (e.g., monkeys,baboons, or chimpanzees), porcine, bovine, horses, goats, sheep, dogs,cats, rabbits, guinea pigs, gerbils, hamsters, rats, or mice. Ofparticular interest as donors are animals (e.g., pigs) that have beengenetically engineered to lack the terminal α-galactose moiety. Fordescriptions of appropriate animals see co-pending U.S. application Ser.No. 10/896,594 and U.S. Pat. No. 6,166,288, the disclosures of all ofwhich are incorporated herein by reference in their entirety.

As an example of suitable porcine-derived tissue, non-limiting mentionis made of STRATTICE™, which is a porcine dermal tissue produced byLifecell Corporation (Branchburg, N.J.). The tissue matrix may bederived from porcine skin by removing the epidermis while leaving thedermal matrix substantially intact. In some embodiments, theporcine-derived tissue matrix may facilitate tissue ingrowth andremodeling with the patient's own cells. In other embodiments, thematerial can include a collagenous matrix derived from human cadaverskin (e.g. ALLODERM®, Lifecell Corporation (Branchburg, N.J.)) that hasbeen processed to remove both the epidermis and cells.

In some embodiments of the present disclosure, a freeze dried ATM isproduced from human dermis by the LifeCell Corporation (Branchburg,N.J.) and marketed in the form of small sheets as ALLODERM®. Such sheetsare marketed by the LifeCell Corporation as rectangular sheets with thedimensions of, for example, 1 cm×2 cm, 3 cm×7 cm, 4 cm×8 cm, 5 cm×10 cm,4 cm×12 cm, and 6 cm×12 cm. The cryoprotectant used for freezing anddrying ALLODERM® is a solution of 35% maltodextrin and 10 mMethylenediaminetetraacetate (EDTA). Thus, the final dried productcontains about 60% by weight ATM and about 40% by weight maltodextrin.The LifeCell Corporation also makes an analogous product made fromporcine dermis (designated XENODERM) having the same proportions of ATMand maltodextrin as ALLODERM®.

As an alternative to using such genetically engineered animals asdonors, appropriate tissues and organs can be treated, before or afterdecellularization, with the enzyme α-galactosidase, which removesterminal α-galactose (α-gal) moieties from saccharide chains on, forexample, glycoproteins. Methods of treating tissue with α-galactosidaseto remove these moieties are described in, for example, U.S. Pat. No.6,331,319, the disclosure of which is incorporated herein by referencein its entirety.

In an implementation, either before or after the soft tissue cells arekilled in the ATM, the collagen-containing material is subjected to invitro digestion of the collagen-containing material with one or moreglycosidases, and particularly galactosidases, such as α-galactosidase.In particular, α-gal epitopes are eliminated by enzymatic treatment withα-galactosidases.

The N-acetylactosamine residues are epitopes that are normally expressedon human and mammalian cells and thus are not immunogenic. The in vitrodigestion of the collagen-containing material with glycosidases may beaccomplished by various methods. For example, the collagen-containingmaterial can be soaked or incubated in a buffer solution containingglycosidase. Alternatively, a buffer solution containing the glycosidasecan be forced under pressure into the collagen-containing material via apulsatile lavage process.

Elimination of the α-gal epitopes from the collagen-containing materialmay diminish the immune response against the collagen-containingmaterial. The α-gal epitope is expressed in non-primate mammals and inNew World monkeys (monkeys of South America) as 1×106-35×106 epitopesper cell, as well as on macromolecules such as proteoglycans of theextracellular components. U. Galili et al., J. Biol. Chem. 263: 17755(1988). This epitope is absent in Old World primates (monkeys of Asiaand Africa and apes) and humans, however. Id. Anti-gal antibodies areproduced in humans and primates as a result of an immune response toα-gal epitope carbohydrate structures on gastrointestinal bacteria. U.Galili et al., Infect. Immun. 56: 1730 (1988); R. M. Hamadeh et al., J.Clin. Invest. 89: 1223 (1992).

Since non-primate mammals (e.g., pigs) produce α-gal epitopes,xenotransplantation by injection of collagen-containing material fromthese mammals into primates often results in rejection because ofprimate anti-Gal binding to these epitopes on the collagen-containingmaterial. The binding results in the destruction of thecollagen-containing material by complement fixation and by antibodydependent cell cytotoxicity. U. Galili et al., Immunology Today 14: 480(1993); M. Sandrin et al., Proc. Natl. Acad. Sci. USA 90: 11391 (1993);H. Good et al., Transplant. Proc. 24: 559 (1992); B. H. Collins et al.,J. Immunol. 154: 5500 (1995). Furthermore, xenotransplantation resultsin major activation of the immune system to produce increased amounts ofhigh affinity anti-gal antibodies. Accordingly, the substantialelimination of α-gal epitopes from cells and from extracellularcomponents of the collagen-containing material, and the prevention ofreexpression of cellular α-gal epitopes can diminish the immune responseagainst the collagen-containing material associated with anti-galantibody binding to α-gal epitopes.

ATMs suitable for use in the present disclosure may be provided invarious forms depending on the tissue or organ from which it is derived,the nature of the recipient tissue or organ, and the nature of thedamage or defect in the recipient tissue or organ. Thus, for example, aATM derived from a heart valve can be provided as a whole valve, assmall sheets or strips, or as pieces cut into any of a variety of shapesand/or sizes. The same concept applies to ATM produced from any of theabove-listed tissues and organs. In some embodiments, the ATM is madefrom a recipient's own collagen-based tissue.

ATM's suitable for use in the present disclosure can be produced by avariety of methods, so long as their production results in matrices withthe above-described biological and structural properties. Asnon-limiting examples of such production methods, mention is made of themethods described in U.S. Pat. Nos. 4,865,871; 5,366,616, and 6,933,326,U.S. patent application Publication Nos. US 2003/0035843 A1, and US2005/0028228 A1, all of which are incorporated herein by reference intheir entirety.

In general, the steps involved in the production of an ATM includeharvesting the tissue from a donor (e.g., a human cadaver or any of theabove-listed mammals), chemical treatment so as to stabilize the tissueand avoid biochemical and structural degradation together with, orfollowed by, cell removal under conditions which similarly preservebiological and structural function. After thorough removal of deadand/or lysed cell components that may cause inflammation as well as anybioincompatible cell-removal agents, the matrix can be treated with acryopreservation agent and cryopreserved and, optionally, freeze dried,again under conditions necessary to maintain the described biologicaland structural properties of the matrix. After freeze drying, the tissuecan, optionally, be pulverized or micronized to produce a particulateATM under similar function-preserving conditions. After cryopreservationor freeze-drying (and optionally pulverization or micronization), theATM can be thawed or rehydrated, respectively. All steps are generallycarried out under aseptic, preferably sterile, conditions.

The initial stabilizing solution arrests and prevents osmotic, hypoxic,autolytic, and proteolytic degradation, protects against microbialcontamination, and reduces mechanical damage that can occur with tissuesthat contain, for example, smooth muscle components (e.g., bloodvessels). The stabilizing solution may contain an appropriate buffer,one or more antioxidants, one or more oncotic agents, one or moreantibiotics, one or more protease inhibitors, and in some cases, asmooth muscle relaxant.

The tissue is then placed in a processing solution to remove viablecells (e.g., epithelial cells, endothelial cells, smooth muscle cells,and fibroblasts) from the structural matrix without damaging thebasement membrane complex or the biological and structural integrity ofthe collagen matrix. The processing solution may contain an appropriatebuffer, salt, an antibiotic, one or more detergents (e.g., Triton-x-100,sodium deoxycholate, polyoxyethylene (20) sorbitan mono-oleate), one ormore agents to prevent cross-linking, one or more protease inhibitors,and/or one or more enzymes. The tissue is then treated with a processingsolution containing active agents, and for a time period such that thestructural integrity of the matrix is maintained.

Alternatively, the tissue can be cryopreserved prior to undergoing waterreplacement. If so, after decellularization, the tissue is incubated ina cryopreservation solution. This solution may contain at least onecryoprotectant to minimize ice crystal damage to the structural matrixthat could occur during freezing. If the tissue is to be freeze dried,the solution may also contain at least one dry-protective components, tominimize structural damage during drying and may include a combinationof an organic solvent and water which undergoes neither expansion norcontraction during freezing. The cryoprotective and dry-protectiveagents may be the same. If the tissue is not going to be freeze dried,it can be frozen by placing it (in a sterilized container) in a freezerat about −80° C., or by plunging it into sterile liquid nitrogen, andthen storing at a temperature below −160° C. until use. The tissuesample can be thawed prior to use by, for example, immersing a sterilenon-permeable vessel (see below) containing the sample in a water bathat about 37° C. or by allowing the tissue to come to room temperatureunder ambient conditions.

If the tissue is to be frozen and freeze dried, following incubation inthe cryopreservation solution, the tissue may be packaged inside asterile vessel that is permeable to water vapor yet impermeable tobacteria, e.g., a water vapor permeable pouch or glass vial. As anon-limiting example, one side of the pouch may include medical gradeporous TYVEK® membrane, a trademarked product of DuPont Company ofWilmington, Del. This membrane is porous to water vapor and imperviousto bacteria and dust. The TYVEK membrane is heat sealed to animpermeable polyethylene laminate sheet, leaving one side open, thusforming a two-sided pouch. The open pouch is sterilized by irradiationprior to use. The tissue is aseptically placed (through the open side)into the sterile pouch. The open side is then aseptically heat sealed toclose the pouch. The packaged tissue is henceforth protected frommicrobial contamination throughout subsequent processing steps.

The vessel containing the tissue is cooled to a low temperature at aspecified rate which is compatible with the specific cryoprotectantformulation to minimize the freezing damage. See U.S. Pat. No. 5,336,616for non-limiting examples of appropriate cooling protocols. The tissueis then dried at a low temperature under vacuum conditions, such thatwater vapor is removed sequentially from each ice crystal phase.

At the completion of the drying of the samples in the water vaporpermeable vessel, the vacuum of the freeze drying apparatus is reversedwith a dry inert gas such as nitrogen, helium or argon. While beingmaintained in the same gaseous environment, the semipermeable vessel isplaced inside an impervious (i.e., impermeable to water vapor as well asmicroorganisms) vessel (e.g., a pouch) which is further sealed, e.g., byheat and/or pressure. Where the tissue sample was frozen and dried in aglass vial, the vial is sealed under vacuum with an appropriate inertstopper and the vacuum of the drying apparatus reversed with an inertgas prior to unloading. In either case, the final product ishermetically sealed in an inert gaseous atmosphere.

After rehydration of the ATM (see below), histocompatible, viable cellscan be restored to the ATM to produce a permanently accepted graft thatmay be remodeled by the host. In one embodiment, histocompatible viablecells may be added to the matrices by standard in vitro cell coculturingtechniques prior to transplantation, or by in vivo repopulationfollowing transplantation. In vivo repopulation can be by therecipient's own cells migrating into the ATM or by infusing or injectingcells obtained from the recipient or histocompatible cells from anotherdonor into the ATM in situ.

The cell types chosen for reconstitution may depend on the nature of thetissue or organ to which the ATM is being remodeled. For example, thereconstitution of full-thickness skin with an ATM often requires therestoration of epidermal cells or keratinocytes. Thus, cells deriveddirectly from the intended recipient can be used to reconstitute an ATMand the resulting composition grafted to the recipient in the form of ameshed split-skin graft. Alternatively, cultured (autologous orallogeneic) cells can be added to the ATM. Such cells can be, forexample, grown under standard tissue culture conditions and then addedto the ATM. In another embodiment, the cells can be grown in and/or onan ATM in tissue culture. Cells grown in and/or on an ATM in tissueculture can have been obtained directly from an appropriate donor (e.g.,the intended recipient or an allogeneic donor) or they can have beenfirst grown in tissue culture in the absence of the ATM.

The endothelial cell is important for the reconstitution of heart valvesand vascular conduits. Such cells line the inner surface of the tissue,and may be expanded in culture. Endothelial cells may also be derived,for example, directly from the intended recipient patient or fromumbilical arteries or veins.

Other non-limiting examples of cells that may be used to reconstitutethe ATMs of the present disclosure include fibroblasts, embryonic stemcells (ESC), adult or embryonic mesenchymal stem cells (MSC),prochondroblasts, chondroblasts, chondrocytes, pro-osteoblasts,osteocytes, osteoclasts, monocytes, pro-cardiomyoblasts, pericytes,cardiomyoblasts, cardiomyocytes, gingival epithelial cells, orperiodontal ligament stem cells. Naturally, the ATM can be repopulatedwith combinations of two more (e.g., two, three, four, five, six, seven,eight, nine, or ten) of these cell-types.

Reagents and methods for carrying out all the above steps are known inthe art. Suitable reagents and methods are described in, for example,U.S. Pat. No. 5,336,616.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A medical implant for surgical breast procedures,comprising: a sheet-like sample of biocompatible material; wherein thesample of biocompatible material includes a first edge and a secondedge; wherein, when the sample of biocompatible material is in a planarconfiguration, the first edge includes a convex portion that curves awayfrom the second edge and the second edge includes a convex portion thatcurves away from the first edge; wherein the convex portion of the firstedge includes a first vertex and the convex portion of the second edgeincludes a second vertex; wherein the sample of biocompatible materialincludes a longitudinal axis coincident with the sample of biocompatiblematerial and a vertical axis coincident with the sample of biocompatiblematerial, the vertical axis passing through the first and secondvertices, and a distance along the longitudinal axis of the sample ofbiocompatible material being longer than a distance along the verticalaxis of the sample of biocompatible material; wherein the vertical axisand the longitudinal axis are orthogonal to each other; wherein theconvex portion of the first edge has a first radius of curvature and theconvex portion of the second edge has a second radius of curvature, thefirst radius of curvature being different from the second radius ofcurvature; wherein the sample of biocompatible material is symmetricalabout the vertical axis; wherein the sample of biocompatible materialcomprises an acellular tissue matrix; wherein the sample ofbiocompatible material has a set of perforations, the set ofperforations including elongate slits arranged across at least a portionof the sample of biocompatible material, wherein ends oflongitudinally-neighboring elongate slits are arranged adjacent to eachother; and wherein the set of perforations forms an arcuate patternextending along the longitudinal axis when the sheet-like sample ofbiocompatible material is in the planar configuration.
 2. The medicalimplant of claim 1, wherein the sample of biocompatible material isbiconvex in shape.
 3. The medical implant of claim 1, wherein the firstedge is substantially parabolicly curved.
 4. The medical implant ofclaim 1, wherein the second edge is substantially parabolicly curved. 5.The medical implant of claim 1, wherein the first edge further includesa nonconvex portion.
 6. The medical implant of claim 1, wherein thesecond edge further includes a nonconvex portion.
 7. The medical implantof claim 1, wherein the second edge further includes a straight portion.8. The medical implant of claim 1, wherein the first edge and the secondedge are joined at apexes, and wherein at least one of the apexes isrounded.
 9. The medical implant of claim 1, wherein the first edge andthe second edge are joined at apexes, and wherein at least one of theapexes is squared.
 10. The medical implant of claim 1, wherein thesample of biocompatible material is symmetrical about at least one axis.11. The medical implant of claim 1, wherein the sample of biocompatiblematerial is asymmetrical about the longitudinal axis.
 12. The medicalimplant of claim 1, wherein the first vertex of the first edge isseparated from a first focus of the first edge by a first length and thesecond vertex of the second edge is separated from a second focus of thesecond edge by a second length, the second length being greater than thefirst length.
 13. The medical implant of claim 1, wherein the acellulartissue matrix comprises a decellularized collagen-containing tissuematrix from a nonhuman animal.
 14. The medical implant of claim 13,wherein the nonhuman animal is a pig.
 15. The medical implant of claim13, wherein the nonhuman animal is genetically modified such thattissues in the human animal lack galactose α-1,3-galactose epitopes. 16.The medical implant of claim 1, wherein the acellular tissue matrixlacks an epithelial basement membrane.
 17. The medical implant of claim1, wherein the acellular tissue matrix is a dermal tissue matrix. 18.The medical implant of claim 1, wherein the set of perforations isarranged in a semicircular pattern.
 19. The medical implant of claim 1,wherein the set of perforations creates a mesh pattern.
 20. The medicalimplant of claim 1, wherein the set of perforations includes a series ofparallel slits, wherein the slits have a generally uniform length,wherein a generally uniform gap distance separateslongitudinally-adjacent slits, and wherein a generally uniformhorizontal separation distance separates adjacent parallel slits. 21.The medical implant of claim 20, wherein the length is between 0.1 and20 mm.
 22. The medical implant of claim 20, wherein the length isbetween 4 and 8 mm.
 23. The medical implant of claim 20, wherein the gapdistance is between 0.1 and 20 mm.
 24. The medical implant of claim 20,wherein the gap distance is between 2 and 6 mm.
 25. The medical implantof claim 20, wherein the horizontal separation distance is between 0.1and 20 mm.
 26. The medical implant of claim 20, wherein the horizontalseparation distance is between 2 and 6 mm.
 27. The medical implant ofclaim 20, wherein adjacent parallel slits are offset longitudinally withrespect to each other.
 28. The medical implant of claim 1, wherein theindividual perforations are arcuate.
 29. A method of making a graftimplant, comprising: providing a sheet of biocompatible material;cutting a graft implant from the sheet of biocompatible material that issized and shaped for conforming to a portion of a surface of a breastimplant having a predetermined volume; and forming a set of perforationsin the graft implant, the set of perforations including elongate slitsarranged across at least a portion of the graft implant, wherein ends oflongitudinally-neighboring elongate slits are arranged adjacent to eachother; wherein, when the graft implant is in a planar configuration, thegraft implant includes a first edge and a second edge, the first edgeincludes a convex portion that curves away from the second edge, and thesecond edge includes a convex portion that curves away from the firstedge; wherein the convex portion of the first edge includes a firstvertex and the convex portion of the second edge includes a secondvertex; wherein the graft implant includes a longitudinal axiscoincident with the graft implant and a vertical axis coincident withthe graft implant, the vertical axis passing through the first andsecond vertices, and a distance along the longitudinal axis of the graftimplant being longer than a distance along the vertical axis of thegraft implant; wherein the vertical axis and the longitudinal axis areorthogonal to each other; wherein the convex portion of the first edgehas a first radius of curvature and the convex portion of the secondedge has a second radius of curvature, the first radius of curvaturebeing different from the second radius of curvature; wherein the graftimplant is symmetrical about the vertical axis; wherein the sheet ofbiocompatible material comprises an acellular tissue matrix; and whereinthe set of perforations forms an arcuate pattern when the graft implantis in the planar configuration.
 30. The method of claim 29, wherein thebreast implant is a round implant.
 31. The method of claim 29, whereinthe breast implant is an anatomical implant.
 32. The method of claim 29,wherein the volume of the breast implant is between 400 and 550 cc. 33.The method of claim 29, wherein the volume of the breast implant isbetween 250 and 400 cc.
 34. The method of claim 29, wherein the volumeof the breast implant is between 100 and 250 cc.
 35. The method of claim29, wherein the providing the sheet of biocompatible material comprises:providing a collagen-containing tissue from a nonhuman animal; andprocessing the tissue so as to render the tissue acellular and lackingan epithelial basement membrane, the process resulting in the productionof the acellular tissue matrix.
 36. The method of claim 35, wherein thenonhuman animal is a pig.
 37. The method of claim 35, wherein the tissueis dermis.
 38. The method of claim 35, wherein the nonhuman animal isgenetically modified so that tissues in the nonhuman animal lackgalactose α-1,3-galactose epitopes.
 39. A method of treating tissue,comprising: providing a sheet-like sample of biocompatible material;selecting a tissue site of interest; and applying the sample ofbiocompatible material to the tissue site of interest; wherein thesample of biocompatible material includes a first edge and a secondedge; wherein, when the sample of biocompatible material is in a planarconfiguration, the first edge includes a convex portion that curves awayfrom the second edge and the second edge includes a convex portion thatcurves away from the first edge; wherein the convex portion of the firstedge includes a first vertex and the convex portion of the second edgeincludes a second vertex; wherein the sample of biocompatible materialincludes a longitudinal axis coincident with the sample of biocompatiblematerial and a vertical axis coincident with the sample of biocompatiblematerial, the vertical axis passing through the first and secondvertices, and a distance along the longitudinal axis of the sample ofbiocompatible material being longer than a distance along the verticalaxis of the sample of biocompatible material; wherein the vertical axisand the longitudinal axis are orthogonal to each other; wherein theconvex portion of the first edge has a first radius of curvature and theconvex portion of the second edge has a second radius of curvature, thefirst radius of curvature being different from the second radius ofcurvature; wherein the sample of biocompatible material is symmetricalabout the vertical axis; wherein the sample of biocompatible materialcomprises an acellular tissue matrix; wherein the sample ofbiocompatible material has a set of perforations, the set ofperforations including elongate slits arranged across at least a portionof the sample of biocompatible material, wherein ends oflongitudinally-neighboring elongate slits are arranged adjacent to eachother; and wherein the set of perforations forms an arcuate patternextending along the longitudinal axis when the sheet-like sample ofbiocompatible material is in the planar configuration.
 40. The method ofclaim 39, further comprising suturing the sample of biocompatiblematerial to the tissue site of interest.
 41. The method of claim 39,wherein the tissue site of interest is breast tissue.
 42. The method ofclaim 41, further comprising: suturing a portion of the first edge to alateral fold of the breast tissue; suturing a portion of the first edgeto an inframammary fold of the breast tissue; and suturing a portion ofthe second edge to an inferior edge of a pectoralis major muscle.